In comparison to conventional dosage forms, gastroretentive drug delivery systems (GRDDS) are designed to remain in the stomach for a prolonged and predictable period of time. Consequently, gastric residence time of drug substances is extended and bioavailability improved. GRDDS are beneficial for a number of drugs, like drug substances whose site of action is locally in the stomach and drugs which exhibit a narrow absorption window in the stomach or in the upper part of the small intestine. Moreover, drugs which are degraded in the intestinal or colonic environment, as well as drug substances which are poorly soluble at alkaline pH-values are candidates profiting from GRDDS.
Various mechanisms have been proposed to achieve gastric retention and avoid unpredictable gastric emptying of dosage forms. These approaches include: co-administration of drugs or pharmaceutical excipients influencing gastric motility pattern and thereby delaying gastric emptying process, magnetic systems, mucoadhesive systems, size-increasing systems due to swelling or unfolding, density-controlled systems that either float on gastric contents or sediment, and combination systems.
Pawar et al. (Gastroretentive dosage forms: A review with special emphasis on floating drug delivery systems. Drug Delivery. 2011 February; 18(2):97-110.) considered floating drug delivery systems (FDDS) as an easy and logical approach regarding formulation and technical aspects for the development of GRDDS. FDDS are low-density systems with a density less than density of gastric fluids (˜1.004 g/cm3). Therefore, dosage forms float on gastric contents and are retained in the stomach while releasing drug.
Since the idea of floating dosage forms was introduced by Davis in 1968 (U.S. Pat. No. 3,418,999), many research groups invented different strategies for preparation of FDDS. Floatation is achieved by incorporation of low-density materials, by swelling or by gas generation and entrapment. Due to the fact that excipients with density less than unity provide immediate floating to the delivery device, their use is highly favored for formulation development.
U.S. Pat. No. 3,976,764 discloses an instantly floating tablet, having a hollow sphere based on gelatin coated with several under-coatings, wherein an therapeutically active ingredient is comprised in one of the under-coatings.
DE 35 27 852 A1 discloses a pharmaceutical formulation with a specific density below 1, wherein a substance forming a gel in water is mixed with a pharmaceutically active ingredient and a fat/oil which is solid at room temperature. The gel forming substance being a cellulose-, dextran- or starch derivative.
EP 0 338 861 A2, refers to an antacid compositions with prolonged gastric residence time. The antacid such as Hydrotalcite or Amalgate forming a solid core which is surrounded by a solid external phase containing a hydrophobic substance e.g. an ester of glycerol with palmitic or stearic acid, hydroxylated polyalkene and a non-ionic emulsifier.
EP 0 717 988 A1, refers to a swollen molding which is an expanded structure having a mesh-like cross-section and an apparent density of less than 1, which structure is predominantly an acid-resistant polymer compound and additionally containing at least an auxiliary blowing agent and a drug substance. Because of its mesh-like structure in cross-section, the swollen molding of the invention has a multiplicity of microfine internal pores which are continuous or discontinuous. Said acid-resistant polymer compound are chosen, e.g. from hydroxpropymethylcellulose acetate succinate or phthalate.
U.S. Pat. No. 4,451,260 refers to a multilayered structure comprising a pharmaceutical active ingredient wherein air is entrapped in the multilayered structure, thus promoting flotation.
U.S. Pat. No. 4,814,179 refers to a floating sustained release therapeutic composition. Non-compressed sustained release tablets comprise a hydrocolloid gelling agent, a therapeutically acceptable inert oil, the selected therapeutic agent and water.
The presence of pharmaceutically inert fatty materials having a specific gravity of less than one decrease the hydrophilicity and increase the buoyancy of the dosage form.
Optimal floating tablets have different conflicting characteristics. On the one hand, high porosity to float on stomach contents, on the other hand sufficient hardness to withstand destruction by gastric peristalsis. Further, high porosity having a positive effect on floating have at the same time also the disadvantage that when pores are exposed to the gastric fluid, water can enter the pores and fill them up and even propagate deeper into the pores, particularly when the pores are interconnected. As a consequence the inherent density will increase and thus decrease the floating capability of the tablet and thus provoking sinking of the tablet at a later stage, and bearing the risk of early clearing from the stomach by the know mechanisms such as peristaltic movements. Prior art counter acts this problem by including acids into their formulations in the presence of carbonates. The acids release CO2 when in contact with water and by this effervescent mechanism, the tablets keep floating. The drawback however is, that such tablets are far more quickly dissolved and thus counteract the long residence time in the stomach.
The present invention provides thus for an instantly floating formulation with gastroretentive properties overcoming the drawbacks as currently presented.
The inventors surprisingly found out that particles from the paper industry can serve as novel pharmaceutical excipient exhibiting a highly porous meshwork with lamellar surface structure that grips particles strongly together. Due to its unique properties, functionalized calcium carbonate (FCC) is promising for preparation of FDDS. It offers the possibility to formulate them in to granules, pellets, capsules or to compact them into tablets or mini-tablets at a relative density of less than unity, i.e. less than 1.000 g/cm3.